Misfolded G? is recruited to cytoplasmic dynein by Nudel for efficient clearance.

ABSTRACT: The G?? heterodimer is an important signal transducer. G?, however, is prone to misfolding due to its requirement for G? and chaperones for proper folding. How cells dispose of misfolded G? (mfG?) is not clear. Here, we showed that mfG? was able to be polyubiquitinated and subsequently degraded by the proteasome. It was sequestered in aggresomes after the inhibition of the proteasome activity with MG132. Sustained activation of G?? signaling further elevated cellular levels of the ubiquitinated G?. Moreover, Nudel, a regulator of cytoplasmic dynein, the microtubule minus end-directed motor, directly interacted with both the unubiquitinated and ubiquitinated mfG?. Increasing the levels of both mfG? and Nudel promoted the association of G? with both Nudel and dynein, resulting in robust aggresome formation in a dynein-dependent manner. Depletion of Nudel by RNAi reduced the dynein-associated mfG?, impaired the MG132-induced aggresome formation, and markedly prolonged the half-life of nascent G?. Therefore, cytosolic mfG? is recruited to dynein by Nudel and transported to the centrosome for rapid sequestration and degradation. Such a process not only eliminates mfG? efficiently for the control of protein quality, but may also help to terminate the G?? signaling.

SUBMITTER: Wan Y 

PROVIDER: S-EPMC3391016 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature